U.S. patent number 4,806,564 [Application Number 07/053,774] was granted by the patent office on 1989-02-21 for antihypercholesterolemic beta-lactones.
This patent grant is currently assigned to Merck & Co., Inc.. Invention is credited to John C. Chabala, Michael N. Chang, Yuan-Ching P. Chiang, Donald W. Graham, James V. Heck, Shu S. Yang.
United States Patent |
4,806,564 |
Chabala , et al. |
February 21, 1989 |
Antihypercholesterolemic beta-lactones
Abstract
The compounds of the following structural formula (I) ##STR1##
are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase
inhibitors and useful as antihypercholesterolemic agents for the
treatmet of disease in which the inhibition of cholesterol
biosynthesis would be useful, such as arteriosclerosis,
hyperlipidemia and familial hypercholesterolemia.
Inventors: |
Chabala; John C. (Westfield,
NJ), Chiang; Yuan-Ching P. (Piscataway, NJ), Chang;
Michael N. (Westfield, NJ), Graham; Donald W.
(Mountainside, NJ), Heck; James V. (Scotch Plains, NJ),
Yang; Shu S. (Bridewater, NJ) |
Assignee: |
Merck & Co., Inc. (Rahway,
NJ)
|
Family
ID: |
21986440 |
Appl.
No.: |
07/053,774 |
Filed: |
May 26, 1987 |
Current U.S.
Class: |
514/449; 549/328;
549/263 |
Current CPC
Class: |
C07D
407/06 (20130101); C07D 305/12 (20130101); A61P
43/00 (20180101); A61P 3/06 (20180101) |
Current International
Class: |
C07D
407/06 (20060101); C07D 407/00 (20060101); C07D
305/00 (20060101); C07D 305/12 (20060101); A61K
031/365 (); C07D 305/08 () |
Field of
Search: |
;549/263,327,328
;514/449 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
Other References
Chemical Communications, 1970, p. 639 [(Chem. Abstracts; vol. 73
#55594j (1970)]. .
J. Chem. Soc. (c), 1971, pp. 3888-3890 [(Chem. Abstracts; vol. 76,
#45686)]..
|
Primary Examiner: Hollrah; Glennon H.
Assistant Examiner: Treanor; S.
Attorney, Agent or Firm: DiPrima; Joseph F. Sudol; Michael
C.
Claims
What is claimed is:
1. A compound represented by the following structural formula (I):
##STR27## wherein: R.sup.1 is selected from
(1) hydrogen,
(2) hydroxy,
(3) C.sub.1-6 alkoxy
(4) phenyl,
(5) carboxy,
(6) C.sub.1-6 alkoxycarbonyl,
(7) substituted C.sub.1-6 alkoxycarbonyl in which the substituent
is a phenyl group,
(8) aminocarbonyl,
(9) C.sub.1-6 alkylaminocarbonyl,
(10) substituted C.sub.1-6 alkylaminocarbonyl in which the
substituent is a hydroxy group,
(11) phenylaminocarbonyl,
R.sup.2 is selected from
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) C.sub.1-6 alkyloxy,
(4) C.sub.2-6 alkenyloxy,
(5) formyloxy,
(6) C.sub.1-6 alkylcarbonyloxy,
(7) carboxy C.sub.1-6 alkylcarbonyloxy,
(8) anisyldiphenylmethyloxy,
(9) C.sub.1-6 alkylsulfonyloxy,
(10) aminocarbonyloxy, and
(11) C.sub.1-6 alkylaminocarbonyloxy;
R.sup.3 is selected from
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) C.sub.2-6 alkenyl,
(4) phenyl, or
R.sup.2 and R.sup.3 when taken together with the carbon atom to
which the are attached form C.sub.3-6 carbocyclic ring;
A is selected from
(1) C.sub.6-17 alkylene,
(2) substituted C.sub.6-17 alkylene in which the one or wwo
substituents are
(a) oxo,
(b) epoxy,
(c) geminal dihydroxy,
(d) C.sub.1-6 alkoxy, and
(e) 4-bromophenylhydrazono;
(3) monounsaturated C.sub.6-17 alkylene, and
(4) substituted monounsaturated C.sub.6-17 alkylene in which the
one or two substituents are
(a) oxo,
(b) epoxy,
(c) geminal dihydroxy,
(d) C.sub.1-6 alkoxy, and
(e) 4-bromophenylhydrazono;
(5) C.sub.7-16 aralkylene, wherein the alkyl chain is interupted by
a 1,2-, 1,3-, or 1,4-phenylene moiety,
(6) C.sub.6-18 alkylene, straight or branched chain, interupted by
an oxygen, sulfur or sulfoxide moiety,
(7) a group of the structure ##STR28## where x is 1-4 and Y is O,
S, or SO; or a pharmaceutically acceptable salt thereof.
2. A compound of claim 1 wherein A is C.sub.6-17 alkylene.
3. A compound of claim 2 which is
E-3-methyl-4-(5-phenylpentyl)-2-oxetanone.
4. A compound of claim 2 which is
E-3-methyl-4-(6-phenylhexyl)-2-oxetanone.
5. A compound of claim 2 which is
E-3-methyl-4-(9-phenylnonyl)-2-oxetanone.
6. A compound of claim 2 which is
E-3-methyl-4-decyl-2-oxetanone.
7. A compound of claim 1 wherein A is substituted C.sub.6-17
alkylene.
8. A compound of claim 7 which is 8
-(3-hydroxymethyl-4-oxo-2-oxetanyl-4-methyl-2-octanone.
9. A compound of claim 7 which is
8-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-(4-bromophenylhydrazono)-o
ctane.
10. A compound of claim 7 which is
8-(3-methoxymethyl-4-oxo-2-oxetanyl-4-methyl-2-octanone.
11. A compound of claim 7 which is 8
-(3-methoxymethyl-4-oxo-2-oxetanyl-4-methyl-2-methoxyoctane.
12. A compound of claim 7 which is
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol.
13. A compound of claim 7 which is
E-3-methyl-4-(9-oxodecyl)-2-oxetanone.
14. A compound of claim 1 wherein A is monounsaturated C.sub.6-17
alkylene.
15. A compound of claim 14 which is
E-3-methyl-4-(9-decenyl)-2-oxetanone.
16. A compound of claim 1 wherein A is substituted monounsaturated
C.sub.6-17 alkylene.
17. A compound of claim 16 which is methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-undec
enoate.
18. A compound of claim 16 which is
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-undec
enoic acid.
19. A compound of claim 16 which is methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-unde
cenoate.
20. A compound of claim 16 which is methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-unde
cenoate.
21. A pharmaceutical composition for the treatment of
hypercholesterolemia which comprises a non-toxic effective amount
of a compound of claim 1 and a pharmaceutically acceptable
carrier.
22. A method of inhibiting cholesterol biosynthesis which comprises
the administration to a subject in need of such treatment a
non-toxic therapeutically effective amount of a compound of claim
1.
Description
BACKGROUND OF THE INVENTION
The compound of the formula (I), wherein R.sup.1 is carboxy,
R.sup.2 are hydroxy, and A is
2,4,6-trimethyl-deca-2,4-dien-1,10-diyl,
12-hydroxy-13-hydroxymethyl-3,5,7-trimethyltetradeca-2,4-dien-1,14-dioic
acid 12,14-lactone, was identified as an antibiotic fungal
metabolite in 1970 [Aldridge et al., Chem. Comm., 1970, p. 639].
The methyl ester of this compound and its tetrahydro analog were
disclosed in the structure elucidation of this compound [Aldridge
et al. J. Chem. Soc. (C), 1971, pp. 3888-3891].
Additionally, co-pending patent application Ser. No. 856,316, filed
Apr. 28, 1986 is directed to the antihypercholesterolemic utility
of these known compounds and co-pending patent application Ser.
No.021,848, filed Mar. 4, 1987, discloses novel .beta.-lactone
derivatives and their anti-hypercholesterolemic utility.
SUMMARY OF THE INVENTION
This invention relates to the novel compounds of the formula (I)
and the pharmacological properties of these compounds which have
been found to be HMG-CoA synthase inhibitors and useful as
antihypercholesterolemic agents either as the sole therapeutic
agent or in combination with bile acid sequestrants.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to novel compounds represented by
the following general structural formula (I): ##STR2## wherein:
R.sup.1 is selected from
(1) hydrogen,
(2) hydroxy,
(3) C.sub.1-6 alkoxy,
(4) phenyl,
(5) carboxy,
(6) C.sub.1-6 alkoxycarbonyl,
(7) substituted C.sub.1-6 alkoxycarbonyl in which the substituent
is a phenyl group,
(8) aminocarbonyl,
(9) C.sub.1-6 alkylaminocarbonyl,
(10) substituted C.sub.1-6 alkylaminocarbonyl in which the
substituent is a hydroxy group,
(11) phenylaminocarbonyl,
R.sup.2 is selected from
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) C.sub.1-6 alkyloxy,
(4) C.sub.2-6 alkenyloxy,
(5) formyloxy,
(6) C.sub.1-6 alkylcarbonyloxy,
(7) carboxy C.sub.1-6 alkylcarbonyloxy,
(8) anisyldiphenylmethyloxy,
(9) C.sub.1-6 alkylsulfonyloxy,
(10) aminocarbonyloxy, and
(11) C.sub.1-6 alkylaminocarbonyloxy;
R.sup.3 is selected from
(1) hydrogen,
(2) C.sub.1-6 alkyl,
(3) C.sub.1-6 alkenyl,
(4) phenyl, or
R.sup.2 and R.sup.3 when taken together with the carbon atom to
which the are attached form C.sub.3-6 carbocyclic ring;
A is selected from
(1) C.sub.1-17 alkylene, straight chain or branched chain,
(2) substituted C.sub.1-17 alkylene in which the one or two
substituents are
(a) oxo,
(b) epoxy,
(c) geminal dihydroxy,
(d) C.sub.1-6 alkoxy, and
(e) 4-bromophenylhydrazono;
(3) monounsaturated C.sub.6-17 alkylene, and
(4) substituted mnnounsaturated C.sub.6-17 alkylene in which the
one or two substituents are
(a) oxo,
(b) epoxy,
(c) geminal dihydroxy,
(d) C.sub.1-6 alkoxy, and
(e) 4-bromophenylhydrazono;
(5) C.sub.7-16 aralkylene, wherein the alkyl chain is interupted by
a 1,2-, 1,3-, or 1,4-phenylene moiety,
(6) C.sub.6-18 alkylene, straight or branched chain, interupted by
an oxygen, sulfur or sulfoxide moiety,
(7) a group of the structure ##STR3## where x is 1-4 and Y is O, S,
or SO; and pharmaceutically acceptable salts thereof.
One embodiment of the compounds of the present invention is the
class of compounds of the formula (I) wherein A is C.sub.6-17
alkylene. Exemplifying this embodiment are the following
compounds:
(1) E-3-methyl-4-(5-phenylpentyl)-2-oxetanone
(2) E-3-methyl-4-(6-phenylhexyl)-2-oxetanone
(3) E-3-methyl-4-(9-phenylnonyl)-2-oxetanone
(4) E-3-methyl-4-decyl-2-oxetanone
A second embodiment of the compounds of the present invention is
the class of compounds of the formula (I) wherein A is substituted
C.sub.6-17 alkylene. Exemplifying this embodiment are the following
compounds:
(1) 8-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone
(2)
8-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-(4-bromophenylhydrazono)-o
ctane
(3) 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone
(4)
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane
(5) 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol
(6) E-3-methyl-4-(9-oxodecyl)-2-oxetanone.
A third embodiment of the compounds of the present invention is the
class of compounds of the formula (I) wherein A is monounsaturated
C.sub.6-17 alkylene. Exemplifying this embodiment is the following
compound:
(1) E-3-methyl-4-(9-decenyl)-2-oxetanone.
A fourth embodiment of the compounds of the present invention is
the class compounds of the formula (I) wherein A is substituted
monounsaturated C.sub.6-17 alkylene. Exemplifying this embodiment
are the following compounds:
(1) methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-undec
enoate
(2)
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-undec
enoic acid
(3) methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihdroxy-3,5,7-trimethyl-2-undec
enoate
(4) methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihdroxy-3,5,7-trimethyl-2-undec
enoate
The present invention is also directed to a method of inhibiting
cholesterol biosynthesis which comprises the administration to a
subject in need of such treatment a nontoxic therapeutically
effective amount of a compound represented by the following general
structural formula (I) and pharmaceutically acceptable salts
thereof.
The present invention is also directed to a method of inhibiting
the activity of HMG-CoA synthase enzyme which comprises the
administration to a subject in need of such treatment a nontoxic
therapeutically effective amount of a compound represented by the
general structural formula (I) and pharmaceutically acceptable
salts thereof.
Specifically the compounds of this invention are useful as
antihypercholesterolemic agents for the treatment of
arteriosclerosis, hyperlipidemia, familiar hypercholesterolemia and
the like diseases in humans. They may be administered orally or
parenterally in the form of a capsule, a tablet, an injectable
preparation or the like. It is usually desirable to use the oral
route. Doses may be varied, depending on the age, severity, body
weight and other conditions of human patients but daily dosage for
adults is within a range of from about 20 mg to 2000 mg (preferably
20 to 100 mg) which may be given in two to four divided doses.
Higher doses may be favorably employed as required.
The pharmaceutically acceptable salts of the compounds of this
invention include those formed from cations such as sodium,
potassium, aluminum, calcium, lithium, magnesium, zinc, and from
bases such as ammonia, ethylenediamine, N-methylglucamine, lysine,
arginine, ornithine, choline, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine,
diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and
tetramethylammonium hydroxide.
The compounds of this invention may also be coadministered with
pharmaceutically acceptable nontoxic cationic polymers capable of
binding bile acids in a non-reabsorbable form in the
gastrointestinal tract. Examples of such polymers include
cholestyramine, colestipol and
poly[methyl-(3-trimethylaminopropyl)imino-trimethylene dihalide].
The relative amounts of the compounds of this invention and these
polymers is between 1:100 and 1:15,000.
Wherein R.sup.1 is hydrogen or phenyl and A is not substituted with
an oxo, an epoxy or a 4-bromophenylhydrazono, the compounds of the
formula (I) wherein R.sup.2 is hydrogen, that is the
3-methyl-4-substituted-2-oxetanones, are conveniently prepared from
readily available starting materials as described in the following
synthetic pathway: ##STR4## wherein R.sup.2 is hydrogen.
Ethyl acetate is reacted with an appropriately substituted aldehyde
(1) wherein R.sup.1 is hydrogen or phenyl and A is not substituted
with an oxo, epoxy or 4-bromophenylhydrazono in the presence of two
moles of lithium diisopropylamide to the .beta.-hydroxy ester (2)
in its dianion form. The dianion is alkylated with methyl iodide to
give the .beta.-hydroxy ester. Base hydrolysis of the
.beta.-hydroxy ester (3) to yield (4) is followed by a standard
lactonization to give the compounds of the formula (I) wherein
R.sup.2 is hydrogen. When A is substituted with an oxo, an epoxy or
a 4-bromophenylhydrazono, a mono or diunsaturated is further
elaborated by a selective bromination dehydrobromination followed
by oxidation to the oxo substituted compounds which are transformed
to the epoxy substituted and 4-bromophenylhydrazono substituted
compounds under standard reaction conditions.
The compounds of the formula (I) wherein R.sup.2 is hydroxy or
C.sub.1-6 alkoxy are conveniently prepared from the known compound,
12-hydroxy-13-hydroxymethyl-3,5,7-trimethyltetradeca-2,4-dien-1,14
dioic acid 12,14-lactone (II) or its alkyl ester according to the
following synthetic transformations. ##STR5## When A is substituted
with an epoxy group, the compound of the formula (II) or its
C.sub.1-6 alkyl ester is reacted with m-chloroperbenzoic acid. When
A is substituted with a geminal dihydroxy group, the compound of
the formula (II) or its C.sub.1-6 alkyl ester is reacted with
osmium tetroxide. When A is substituted with an oxo group the
13-C.sub.1-6 alkoxymethyl derivative of the compound of the formula
(II) is reacted with ozone. The 13-C.sub.1-6 alkoxymethyl
derivatives may be prepared by the alkylation of the hydroxymethyl
group with an alkyl halide in the presence of silver oxide. The oxo
substituted compounds can be converted into the C.sub.1-6 alkoxy
substituted compounds by reduction to the hydroxy followed by an
alkylation under standard conditions. The oxo compound can also be
converted into the 4-bromophenylhydrazono compound using standard
reaction conditions.
The intrinsic HMG-CoA synthase inhibition activity of the compounds
of this invention is measured by the standard in vitro protocol
described below:
The livers from male Charles River CD rats (225-350 g) were
homogenized in 0.25 M sucrose which was adjusted with
phenylmethylsulfonylfluoride (PMSF) and N-p-tosyl-1-lysine
chloromethyl ketone (TLCK) so that the final concentration of each
was 50 and 25 mg/ml, respectively. The homogenate was centrifuged
at 15,000.times. g for 20 minutes, the supernatant filtered through
a fine nylon screen to remove most of the fat layer and
recentrifuged at 100,000.times. g for 1 hour. This supernatant was
removed and 1 M potassium phosphate, dithiothreitol (DTT) and
ethylene glycol-bis(.beta.-aminoethyl ether)-N,N,N',N'-tetracetic
acid (EGTA) added to give a final concentration of 0.1 M (pH 7.2),
0.5 mM and 0.1 mM, respectively. Solid ammonium sulfate was added
to 50% saturation to the protein solution, it was centrifuged at
15,000.times. g and the supernatant discarded. This precipitated
protein could be stored at -70.degree. C. for at least one month
with very little loss of activity. The ammonium sulfate precipitate
was dissolved in an minimal mount of 0.06 M potassium phosphate
buffer (pH 7.2) containing 0.5 mM dithiothreitol and 0.1 mM EGTA
(referred to as 0.06 M phosphate buffer) and dialyzed overnight
against 2 liters of the same buffer to remove the ammonium sulfate
and to inactivate HMG-CoA lyase [Clinkenbeard, et al., J. Biol.
Chem. 250, 3108-3116(1975)].
The dialyzed extract was added to a column of DEAE-52 (Whatman)
which had been equilibrated with 0.06 M phosphate buffer (10 mg of
protein to 1 ml bed volume of the resin). The DEAE-cellulose was
eluted with 0.06 M phosphate buffer until the optical density at
280 nm was essentially zero. This fraction contained the
.beta.-ketoacetyl-CoA thiolase activity. The HMG-CoA synthase was
eluted from the column with 0.1 M phosphate buffer (pH 7.2)
containing 0.5 mM DTT and 0.1 mM EGTA, and was virtually free of
all thiolase activity. The protein was precipitated by the addition
of ammonium sulfate to give 50% saturation. This solution was
stirred for 10 minutes at 4.degree. C. and the precipitate
collected by centrifugation at 15,000 rpm for 10 minutes. The
supernatant was discarded and the precipitate dissolved in a
minimum of 0.06 M phosphate buffer, pH 7.2 (about 10 ml) and the
enzyme stored at -80.degree. C.
HMG-CoA Synthase Inhibition Assay
Enzyme protein (ca. 24 mg) was added to a solution containing 117
.mu.M Tris-HCl (pH 8.0), 11.7 .mu.M MgCl.sub.2, 1.17 .mu.M
Ethylenediaminetetraacetic acid (EDTA), 0.58 .mu.M dithiothreitol,
and the indicated concentrations of the test compound (added as a 2
mg/ml solution in dimethylsulfoxide). The incubation took place in
a volume of 0.085 ml at 30.degree. in a shaking water bath. After 5
minutes, 15 ml of a solution containing acetoacetyl-CoA and 0.1
.mu.Ci of 1-[.sup.14 C]-acetyl-CoA was added to give a final
concentrations of 0.1 and 0.4 .mu.M, respectively. The incubation
was continued for 10 more minutes and the reaction stopped by the
addition of 50 ml of the assay mixture to 0.2 ml of 6N HCl in a
glass scintillation vial. The vial was heated for 1 hour at
120.degree. after which time 0.2 ml more of 6N HCl was again added
to each vial and the heating continued for another hour. Following
this, 1.0 ml of 0.9% saline was added to each vial and finally 10
ml of scintillation liquid. Radioactivity was determined in a
Packard Tri-Carb liquid scintillation counter.
Percent inhibition is calculated by the formula: ##EQU1##
IC.sub.50 values were determined by plotting the log of the
concentration of the test compound verses the percentage inhibition
and fitting a straight line to the resulting data by using the
least squares method.
Representative of the intrinsic HMG-CoA synthase inhibitory
activities of the compounds of this invention, tabulated below are
the IC.sub.50 or IC.sub.25 (the inhibitory concentration which
inhibits 50 percent and 25 percent of the HMG-CoA synthase activity
respectively).
______________________________________ Compounds of the Formula (I)
AR.sup.1 R.sub.2 IC.sub.50 ______________________________________
(CH.sub.2)5Ph H 1.4 .times. 10.sup.-6 (CH.sub.2).sub.6 Ph H 1.5
.times. 10.sup.-6 (CH.sub.2).sub.9 Ph H 1.2 .times. 10.sup.-6
(CH.sub.2)9CH.sub.3 H 2.5 .times. 10.sup.-7 ##STR6## OH 1.6 .times.
10.sup.-6 ##STR7## OH 0.8 .times. 10.sup.-6 ##STR8## OCH.sub.3 1.7
.times. 10.sup.-6 ##STR9## OCH.sub.3 5.5 .times. 10.sup.-6
(CH.sub.2).sub.8 CHCH.sub.2 H 1.6 .times. 10.sup.-6 ##STR10## OH
0.8 .times. 10.sup.-7 ##STR11## OH 0.1 .times. 10.sup.-6 ##STR12##
OH 1.1 .times. 10.sup.-6 ##STR13## OCH.sub.3 1.9 .times. 10.sup.-6
______________________________________
The following examples illustrate the preparation of the compounds
and their incorporation into pharmaceutical compositions and as
such are not to be construed as limiting the invention set forth in
the claims appended hereto.
EXAMPLES 1 to 6
Preparation of E-3-methyl-4-(substituted)-2-oxetanones
1. Ethyl threo-3-hydroxy-2-methyl-12-tridecenoate
To 8.6 ml g 1.0M lithium diisopropylamide (LDA), prepared from 2.20
ml of diisopropylamine, 6.3 ml of 2.5N nBuLi in hexane, and 9.5 ml
of THF was added ethyl acetate (0.7325 ml, 7.5 mmoles) dropwise
maintaining the temperature <-45.degree. C. After 10 minutes,
10-undecenal (1.09 g, 6.5 mmoles) was added dropwise keeping the
temperature <-30.degree. C. The temperature was allowed to rise
to -15.degree. C., kept there for 15 minutes, lowered to
-50.degree. C. and 9.4 ml of the above LDA solution was added
maintaining the temperature <-30.degree. C. After 15 minutes at
-20.degree. C., the cooling bath was removed and a solution of MeI
(0.70 ml, 11.25 mmoles) in HMPA (1.75 ml) was added rapidly. After
15 minutes at room temperature, the mixture was warmed at
35.degree. C. for 5 minutes and poured into 1M H.sub.2 SO.sub.4 (45
ml) and Et.sub.2 O (25 ml). The aqueous phase was extracted with
Et.sub.2 O (2.times.), and the combined Et.sub.2 O phases were
washed with H.sub.2 O (2.times.) and saturated brine and dried
(MgSO.sub.4). The crude material after evaporation in vacuo was
flashed chromatographed on silica gel with hexane - EtOAc (9:1) to
give pure ethyl threo-3-hydroxy-2-methyl-12-tridecenoate.
NMR: (CDCl.sub.3).delta. 5.80 (m, 1H, CH.dbd.CH.sub.2), 4.94-5.03
(m, 2H, CH.dbd.CH.sub.2), 4.16 (q, 2H, OCH.sub.2 CH.sub.3), 3.64
(m, 1H, CHOH), 2.57 (d, 1H, OH), 2.50 (m, 1H, CHCH.sub.3), 2.02 (q,
2H, CH.sub.2 CH.dbd.), 1.27 (t, 3H, OCH.sub.2 CH.sub.3), 1.19 (d,
3H, CH.sub.3 CH).
The following compounds were prepared using essentially the same
method:
Ethyl threo-3-hydroxy-2-methyltridecanoate
NMR: .delta. 4.17 (q, 2H, OCH.sub.2 CH.sub.3), 3.64 (brs, 1H,
CHOH), 2.57 (d, 1H, OH), 2.50 (m, 1H, CHCH.sub.3), 1.26 (t, 2H,
OCH.sub.2 CH.sub.3), 1.21 (d, 3H, CHCH.sub.3), 0.88 (t, 3H,
13-CH.sub.3).
Ethyl threo-3-hydroxy-2-methyl-7-phenyloctanoate
NMR: .delta. 7.1-7.4 (m, 5H, ArH), 4.17 (q, 2H, OCH.sub.2
CH.sub.3), 3.64 (brs, 1H, CHOH), 2.61 (t, 2H, CH.sub.2 Ph), 2.48
(m, 2H, CHCH.sub.3), 1.26 (t, 3H, OCH.sub.2 CH.sub.3), 1.20 (d, 3H,
CHCH.sub.3).
Ethyl threo-3-hydroxy-2-methyl-8-phenylnonanoate
NMR: .delta. 7.1-7.4 (m, 5H, ArH), 4.17 (q, 2H, OCH.sub.2
CH.sub.3), 3.62 brs, 1H, CHOH), 2.60 (t, 2H, CH.sub.2 Ph), 2.50 (m,
2H, CHCH.sub.3), 1.27 (t, 3H, OCH.sub.2 CH.sub.3), 1.21 (d, 3H,
CHCH.sub.3).
Ethyl threo-3-hydroxy-2,5,9,13-tetramethyltetradecanoate
NMR: .delta. 4.17 (q, 2H, OCH.sub.2 CH.sub.3), 3.75 (brs, 1H,
CHOH), 2.54 (d, 1H, OH), 2.49 (m, 1H, CHCH.sub.3).
2. E-3-Methyl-4-(6-phenylhexyl)-2-oxetanone
A mixture of ethyl threo-3-hydroxy-2-methyl-8-phenylnonanoate (110
mg) and 1 ml of 1.7M KOH in ethanol-H.sub.2 O (1:1) was stirred at
room temperature in a N.sub.2 atmosphere for 3 hours. The clear
solution was diluted with H.sub.2 O, extracted with Et.sub.2 O,
acidified with concentrated HCl, and extracted with Et.sub.2 O
(3.times. ). The combined Et.sub.2 O extracts were washed with
H.sub.2 O and saturated brine and dried (MgSO.sub.4). Evaporation
in vacuo gave threo-3-hydroxy-2-methyl-8-phenylnonanoic acid.
A solution of threo-3-hydroxy-2-methyl-8-phenylnonanoic acid (88
mg, 0.33 mmole) in pyridine (2 ml) was cooled to -15.degree. C. and
p-toluenesulfonyl chloride (127 mg, 0.66 mmole) was added. After
stirring several minutes, the solution was kept at 3.degree. C. for
20 hours. The red-brown solution was poured onto ice-cold 1M.sub.2
SO.sub.4 -Et.sub.2 O. The aqueous phase was extracted with Et.sub.2
O (2x). The combined Et.sub.2 O phases were washed with H.sub.2 O
saturated NaHCO.sub.3 solution, saturated brine, and dried
(MgSO.sub.4). The residue after evaporation in vacuo was purified
by TLC (silica gel, hexane-EtOAc 9:1) to give
E-3-methyl-4-(6-phenylhexyl)-2-oxtanone. IR 1822 cm.sup.-1
(C.dbd.O); NMR: .delta. 7.1-7.4 (m, 5H, ArH), 4.16 (dxt, 1H, 4-H),
3.22 (dxq, 1H, 3-H, J 3,4=4.0 Hz), 2.60 (t, 2 H, CH.sub.2 Ph), 1.38
(d, 3H, CHCH.sub.3).
The following compounds were prepared using essentially the same
method:
______________________________________ Compound No.
______________________________________ 2
E-3-Methyl-4-decyl-2-oxetanone NMR: .delta. 4.18 (d.times.t, 1H,
4-H), 3.23 (d.times.g, 1H, 3-H, J 3,4,=4.0Hz), 1.41 (d, ##STR14## 3
E-3-Methyl-4-(5-phenylpentyl)-2-oxetanone IR 1825 cm.sup.-1
(C.dbd.O); NMR: .delta. 7.1-7.35 (m, 5H, ArH), 4.15 (d.times.t, 1H,
4-H), 3.20 (d.times.g, 1H, 3-H, J 3,4=4.0 Hz), 2.61 (t, ##STR15## 4
E-3-Methyl-4-(9-decenyl)-2-oxetanone NMR: .delta. 5.81 (m, 1H,
CH.dbd.CH.sub.2), 4.9-5.1 (m, 2H, CH.dbd.CH.sub.2), 4.16
(d.times.t, 1H, 4-H), 3.20 (d.times.q, 1H, 3-H, J 3,4=3.9 Hz), 2.03
(q, 2H, CH2CH.dbd.), 1.37 (d, 3H, ##STR16## 5
E-3-Methyl-4-(9-decynyl)-2-oxetanone IR 1825 cm.sup.-1 (C.dbd.O),
2110 cm.sup.-1 (C.dbd.C). NMR: .delta. 4.17 (d.times.t, 1H, 4-H),
3.22 (d.times. q, 1H, J 3,4=4.0 Hz, 3-H), 2.19 (m, 2H, CH.sub.2
C.dbd.C), 1.94 (t, 1H, C.tbd.CH), ##STR17## 6
E-3-Methyl-4-(9-oxodecyl)-2-oxetanone NMR: .delta. 4.18 (d.times.t,
1H, 4-H), 3.21 (d.times.q, 1H J 3,4=4.0, 3-H), 2.42 (t, 2H,
##STR18## ##STR19## ______________________________________
EXAMPLE 7
Preparation of E-3-Methyl-4-(9-oxodecyl)-2-oxetanone
1. Threo-3-hydroxy-2-methyl-12-tridecynoic acid
To a solution of threo-3-hydroxy-2-methyl-12tridecenoic acid (420
mg, 1.74 mmoles) in CH.sub.2 Cl.sub.2 (2 ml) cooled to 0.degree. C.
was added dropwise Br.sub.2 (94 ml, 1.81 mmoles). The mixture was
kept at room temperature for 10 minutes, and the solvent removed in
vacuo to give the 12,13 dibromo compound.
A solution of the above dibromo compound in 3 ml of Et.sub.2 O was
added to a suspension of NaNH.sub.2 (prepared from 220 mg of Na) in
15 ml of liquid NH.sub.3. After stirring for 4 hours in a N.sub.2
atmosphere, the NH.sub.3 was allowed to evaporate overnight. The
residue was dissolved in concentrated NH.sub.4 OH (20ml) and
filtered. The filtrate was washed with Et.sub.2 O, acidified with
concentrated HCl and extracted with Et.sub.2 O (3.times.). The
combined Et.sub.2 O extracts were washed with H.sub.2 O and
saturated brine and dried (MgSO.sub.4). Evaporation in vacuo gave
threo-3-hydroxy-2-methyl-12-tridecynoic acid.
NMR: .delta.3.70 (brs, 1H, CHOH), 2.56 (m, 1H, CHCH.sub.3), 1.94
(t, 1H, C.sub..dbd..sup.-- CH), 1.24 (d, 3H, CHCH.sub.3).
2. Threo-3-hydroxy-2-methyl-12-oxotridecanoic acid
A solution of threo-3-hydroxy-2-methyl-12-tridecynoic acid (160 mg,
0.67 mmoles) in 1 ml of 90% EtOH was stirred with 50 mg of
Hg/Nafion-H [Synthesis, 671 (1978)] at room temperature for 8 hours
and then at 43.degree. C. for 30 minutes. The resin was filtered
and washed EtOH (2x) and Et.sub.2 O (3x). The filtrate and washes
were diluted with H.sub.2 O and extracted with Et.sub.2 O
(3.times.). The combined Et.sub.2 O extracts were washed with
H.sub.2 O and saturated brine and dried (MgSO.sub.4). Evaporation
in vacuo gave threo-3-hydroxy-2-methyl-12-oxotridecanoic acid.
NMR: .delta. 3.48 (brs, 1H, CHOH), 2.57 (m, 1H, CHCH.sub.3), 2.42
(t, 2H, CH.sub.2 CO), 2.12 (s, 3H, COCH.sub.3), 1.25 (d, 3H,
CHCH.sub.3).
3. E-3-Methyl-4-(9-oxodecyl)-2-oxetanone
Utilizing the general procedure of Example 1, Step 2, the above
noted compound was obtained from
threo-3-hydroxy-2-methyl-12-oxo-tridecanoic acid.
NMR: .delta. 4.18 (dxt, 1H, 4-H), 3.21 (dxq. 1H, J=4.0 H.sub.2
=Hz), 2.42 (t, 2H, CH.sub.2 CO), 2.12 (5, 3H, CH.sub.3 CO), 1.38
(d, 3H, CH.sub.3 CH).
EXAMPLE 8
Preparation of
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone
To a solution of 400 mg (1.135 mmole) of methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)3,5,7-trimethyl-2,4-undecadienoate
in 10 ml of CHCl.sub.2 at -78.degree. C., was bubbled ozone for 8
minutes. The resulting mixture was stirred for 30 minutes at
-78.degree. C. then at room temperature for another 30 minutes.
Acetic acid and zinc dust were added. After stirring for 1 hour at
room temperature, the solution was filtered and the filtrate was
concentrated to dryness. The product was purified by flash column
chromatography to give
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone as a
colorless oil. ##STR20##
EXAMPLE 9
Preparation of
8-(3-methoxymethyl-4-oxo-2-oxetanyl)4-methyl-2-octanol
40 mg (0.156 mmole) of
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanone in 5 ml of
MeOH, was added 10 mg of sodium borohydride. The mixture was
stirred for 5 minutes at room temperature. The product as purified
by flash column chromatography (30% ETOAc in hexane) to afford
8-(3-methoxymethyl-4-oxo-2-oxetanyl-4-methyl-2-oxetanol as an oil.
##STR21##
EXAMPLE 10
Preparation of
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane
10 mg of 8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-octanol in
1 ml of EtOAc was added a small amount of activated silver oxide
and 0.5 ml of methyl iodide. The mixture was heated for 5.5 hours
at N 60.degree. C. The solution was filtered and the filtrate was
concentrated to dryness. The product was purified by flash
chromatography to yield
8-(3-methoxymethyl-4-oxo-2-oxetanyl)-4-methyl-2-methoxyoctane.
##STR22##
EXAMPLE 11
Preparation of
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-4,5,7-trimethyl-2-undec
enoic acid
65 mg (0.20 mmole) of
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoic
acid in 3 ml of CH.sub.2 Cl.sub.2 was added 0.12 mg (0.7 mmole) of
m-chloro-peroxybenzoic acid. The resulting mixture was strred for 2
hours at room temperature. The product was purified by prep. TLC
(5% MeOH in CH.sub.2 Cl.sub.2) to yield
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-undec
enoic acid. ##STR23##
EXAMPLE 12
Preparation of
Methyl-11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-
2-undecenoate
Similarly, following the procedure of Example 11, but substituting
methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate
for 11-(3-hydroxoymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl
2,4-undecadienoic acid yielded methyl
11-(3-(hydroxymethyl)-4-oxo-2-oxetanyl)-4,5-oxiranyl-3,5,7-trimethyl-2-und
ecenoate. ##STR24##
Mass spectrum M/l=355 (m7).
EXAMPLE 13
Preparation of
Methyl-11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl
-2-undecenoate
To a solution of 20 mg (0.059 mmole) of methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate
in 3 ml of EtOAc at 0.degree. C. was added 100 ml of pyridine, then
added 200 ml of osmium tetroxide-ether solution (1 g/10 ml, 20 mg).
The mixture was stirred for 1 hour at 0.degree. C., then 1 hour at
room temperature until the solution turned brown. The solution was
concentrated to dryness. The residue was redissolved in 10 ml of
CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 solution then was added to
an aqueous sodium bisulfate solution (1 g in 8 ml of H.sub.2 O).
The mixture was stirred overnight. The organic layer was separated,
dried and concentrated. The product was purified by prep. TLC
(hexane:EtOAc=1:1) to give methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-unde
cenoate. ##STR25##
EXAMPLE 14
Preparation of
Methyl-11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl
-2-undecenoate
10 mg of methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-unde
cenoate in 2 ml of EtOAc was added 35 mg of silver oxide and 0.3 ml
of methyl iodide. The mixture was heated at 53.degree. C.
overnight. The solution was filtered and concentrated by dryness.
The product was purified by prep. TLC (EtOAc:Hexane=1:1) to afford
methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-4,5-dihydroxy-3,5,7-trimethyl-2-unde
cenoate. ##STR26##
EXAMPLE 15
Preparation of
methyl-11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate
1. Methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenaote
49 mg (0.144 mmole) of Methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate
in 5 ml of EtOAc was added 3 mg of platinium oxide. This mixture
was hydrogenated at room temperature and 1 atom for N30 minutes
(NO. 144 mmole (1 eq) of hydrogen was consumed). The solution was
filtered and the filtrate was concentrated to dryness afforded
methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate.
NMR (CDCl.sub.3): .delta. 0.83(m,6H), 5.62(s,1H).
2. Methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate
Similarly, following the procedure of Example 16, Step 1, but
substituting methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2,4-undecadienoate
for methyl
11-(3-hydroxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-1,4-undecadienoate,
afforded methyl
11-(3-methoxymethyl-4-oxo-2-oxetanyl)-3,5,7-trimethyl-2-undecenoate.
EXAMPLE 16
Preparation of Alkali and Alkaline Earth Salts of Compound I
wherein R.sup.1 is carboxy
To a solution of the lactone from Example 1 (42 mg) in ethanol (2
ml) is added aqueous NaOH (1 equivalent). After one hour at room
temperature, the mixture is taken to dryness in vacuo to yield the
sodium salt of Compound I, wherein R.sup.1 is carboxy.
In like manner, the potassium salt is prepared using one equivalent
of potassium hydroxide, and the calcium salt using one equivalent
of CaO.
EXAMPLE 17
As a specific embodiment of an oral composition of a compound of
this invention, 20 mg of the lactone from Example 1 is formulated
with sufficient finely divided lactose to provide a total amount of
580 to 590 mg to fill a size 0 hard gelatin capsule.
EXAMPLE 18
As a specific embodiment of a parenteral composition of a compound
of this invention, 20 mg of the lactone from Example 1, as the
sodium salt, is dissolved in sterile water, buffered to a pH of 7
with 1.0 mM potassium phosphate buffer solution to a concentration
of 2.0 percent and is placed in a sterile ampule for parenteral
administration.
* * * * *